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Lombardi was born to a concert pianist and an Italian actress living in New York City. His family soon moved back to Rome, Italy where he lived until the age of six. He went on to attend Buckley Country Day School and public schools in Great Neck, New York and elsewhere on Long Island. In 1974 Lombardi began his undergraduate studies at Dowling College and graduated cum laude in the Biology major and Physics minor in 1977. He attended Graduate School at Clemson University where he received his MA in 1980 and was granted a PhD in Zoology in 1983.

Upon graduation, Lombardi accepted a postdoctoral appointment and lectureship in the biological sciences at the University of North Carolina which he held until 1986. In 1986, Lombardi was appointed an Assistant Professor of Biology at the University of North Carolina at Greensboro. In 1990, he received tenure and was named Director of Graduate Studies in Biology. He served on the faculty at the University of North Carolina at Greensboro until 1999. Lombardi also served as Director of the University's Analytical Visualization Center from 1993 to 1999. From 2002 to 2005, Lombardi managed a research and development group at the University of Wisconsin–Madison that specialized in the design and development of open source virtual learning environments and digital media technologies for learning and instruction. Currently Lombardi is an Assistant Vice President with Duke University's Office of Information Technology. He is also a Senior Research Scholar with Duke University's program in Information Science + Information Studies,[1] and an adjunct professor with Duke University's Department of Computer Science.

Lombardi's early research program centered on the evolution of complex organismal function in vertebrates and the evolution of maternal-embryonic physiological relationships. An advocate of the use of imaging technologies and early adopter of information technology in university teaching and learning, in 1987 Lombardi began writing HyperTalk-based software applications in support of learning and instruction in anatomy and physiology. In the mid-1990s, Lombardi combined his interests in information technology, complex systems, and the phenomenon of emergence in biological systems to begin designing and developing computer-supported collaboration systems involving self-optimizing massively multiuser online 3D environments.

Lombardi eventually founded ViOS, Inc. where, during the period from 1999–2001, he served as the venture capital-backed company's first CEO and then Chief Creative Officer/Software architect. There, he and his team designed and implemented ViOS, a client–server technology that enabled the first 3Duser interface to network deliverable resources (including the Internet) in the form of a highly customizable and massively multi-user online virtual environment – essentially a very large scale social software system/3Dwiki.

Lombardi is one of the six principal architects of the Croquet software developer's toolkit and from 2006–2008 he served as Executive Director of the Croquet Consortium,[3] a not-for-profit organization to promote the adoption of Croquet open source software technologies.

Lombardi is presently leading a National Science Foundation funded effort to develop Open Cobalt, an open source and multi-platform metaverse browser and toolkit application and toolset to support the large scale visualization and simulation needs of educators and researchers. Open Cobalt is being made available in the open source as a way of fostering a viable community-based software development effort leading to open virtual world technologies supporting the needs of research and education.